Eosinophilic esophagitis (EE) is an emerging worldwide disease, as documented by recent case series from Switzerland, Australia, Canada, Japan, England, and the U.S. Of concern, EE appears to be a growing health problem with an annual incidence of at least 1:10,000 children. The primary symptoms of EE (chest and abdominal pain, dysphagia, heartburn, vomiting, and food impaction) are also observed in patients with chronic esophagitis (CE) including gastroesophageal reflux disease (GERD). EE poses considerable diagnostic and therapeutic challenges especially because esophageal eosinophilia has been associated with several other medical condition including GERD, parasitic infection, and hypereosinophilic syndromes. In contrast to GERD, EE is more likely in males (80%), appears to have a not uncommon familial form, has a high rate of associated atopic disease (70%), and is typically not associated with abnormal pH probing of the esophagus. Distinguishing EE from GERD is important since EE patients typically do not respond to anti-GERD therapy, but rather respond to anti-inflammatory therapy and/or allergen elimination. Whereas both GERD and EE are associated with esophageal eosinophils, the level of eosinophils in EE is much higher; it has been proposed that the diagnosis of EE requires greater than 24 eosinophils per high-powered field (×40) from an esophageal tissue biopsy since these levels have been associated with non-responsiveness to anti-GERD therapy. However, whether GERD and EE representative a continuum, with EE being a more severe manifestation has not been addressed. A more clear differentiation between these various esophagitis states is needed.
Experimental dissection of experimental EE models in mice have revealed that EE can be triggered by both food and aeroallergens, particularly when the esophageal disease is co-induced with respiratory inflammation. However, nearly 25% of patients with EE are non-atopic individuals with no identifiable allergic sensitization. A question is to understand the relationship between the atopic and non-atopic variants of EE; whether atopic and non-atopic esophagitis involves similar effector pathways has implications for therapeutic strategies. Murine modeling has established that EE is a Th2 associated disease. IL-5 is required for disease pathogenesis; a humanized anti-IL-5 appears to be effective in an early clinical study. Human EE is associated with over-production of the Th2 cytokines IL-4 and IL-13. However, although these Th2 cytokines have been implicated, the mechanism by which they lead to esophageal eosinophilia is unclear. While IL-4 and IL-13 are known to induce the eosinophil specific eotaxin chemokines (e.g. eotaxin-1, eotaxin-2, eotaxin-3), their role has remained elusive since they have yet been demonstrated to be over-produced in EE and eotaxin-1 deficient mice only develop a modest attenuation of experimental EE. Based on homology with allergic inflammation in the lung, which involves the interplay of at least 17 chemokines including all three eotaxins, the inflamed esophagus may also involve a myriad of chemokines, with no dominance of a single chemokine.